Dopamine is a neurotransmitter essential for neuronal signal transduction in animal brains including humans. Dopamine receptor antagonists inhibiting the binding between dopamine and its cognate receptors have been used as a therapeutic agent for treating central nervous system (CNS) disorders such as schizophrenia. Since the discovery of psychotropic effect chloropromazine in 1952, numerous psychotropic drugs with various chemical structures have been developed. Drugs such as chloropromazine and haloperidol, which typically work on dopamine D2 receptors, are shown to have generally good therapeutic profiles for the treatment of schizophrenia. However, their clinical applications are greatly restricted because they are known to cause extrapyramidal side effects (EPS) in addition to other adverse effects such as sexual dysfunction, orthostatic hypotension, excessive sedation and gain in body weight, thus preventing patients from managing a normal life. Further, these drugs are shown to improve the symptoms of schizophrenia such as delusion or hallucination but were unable to improve apathy, atrophy and impairment of cognitive function at all [Wong, A. H. C. et al., Expert. Opin. Ther. Targets 1999, 3, 571-586; Chatterjee, A. et al., Am. J. Psychiat. 1995, 152, 1724-1729]. Therefore, there has been a longfelt need for the development of a new version of drug that can remedy the above-mentioned drawbacks of the typical therapeutic drugs for the treatment of mental disorders. As a result, atypical psychotropic drugs such as clozapine, olanzapine, risperidone, quetiapine and aripiprazole have been developed recently to meet the above requirement. Among them, the most representative D4 antagonist is clozapine. Clozapine has shown a relatively low affinity for dopamine D2 receptor but a relatively high selectivity for dopamine D4 receptor. It also manifested a high affinity for serotonin (5-HT) receptor such as 5-HT6 in several reports (Van Tol, H. H. M et al., Nature 1991, 350, 610-614; Oak, J. N. et al., Eur. J. Pharmacol. 2000, 405, 303-327). Clozapine is known to have relatively reduced side effects compared with those of typical drugs acting on dopamine D2 receptors. However, it still has extrapyramidal side effects (EPS) and shows no efficacy in about 30-50% of patients. Based on these findings, intensive researches have been recently performed to develop the dopamine D4 receptor antagonists with an improved selectivity for the D4 receptor or the antagonists showing a moderate affinity for serotonin 5-HT2 receptor in addition (Lober, S. et al., Bioorg. Med. Chem. Lett. 2006, 16, 2955-9; Bartolome, J. M. et al., Bioorg. Med. Chem. Lett. 2005, 15, 2898-901; Arora, J. et al., Bioorg. Med. Chem. Lett. 2005, 15, 5253-5256; Nakane, M. et al., Neuropharmacology 2005, 49, 112-121). Meanwhile, dopamine receptors have been reported to be closely associated with schizophrenia, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), depression, dementia, migraine, aggressive and suicidal behaviors (Todd, R. D. & O'Malley, K. L., TIPS 2001, 55-56; Roth, B. L. et al., Psychopharmacology 2004, 174, 17-24).
The inventors of the present invention synthesized novel piperazinyl-propyl-pyrazole compounds having high affinity for the dopamine D4 receptor and completed the present invention by confirming that these compounds indeed have high affinity for the dopamine receptor.
Therefore, in an embodiment, the present invention provides novel piperazinyl-propyl-pyrazole derivatives with a novel structure introduced with various substituents, and its pharmaceutically acceptable salt.
In another embodiment, the present invention provides a novel piperazinyl-propyl-pyrazole derivative and a method of its preparation.
In a further embodiment, the present invention provides a pharmaceutical composition comprising a novel piperazinyl-propyl-pyrazole derivative as an active ingredient effective in the prevention and treatment of CNS disorders.